Abstract/Summary Inappropriate accumulation of fat in the liver leads to hepatic insulin resistance and inflammation which can progress to liver fibrosis. Therefore, understanding the mechanisms regulating hepatic lipid metabolism is critical in optimizing the diagnosis and treatment of metabolic diseases that are common in the Veteran population including obesity, diabetes mellitus and hyperlipidemia. In that the liver is a major target of growth hormone (GH), coupled with the fact that developmental- and disease-associated changes in GH secretion/action are associated with alterations in hepatic lipid accumulation, understanding how GH regulates hepatic lipid metabolism is clinically relevant. A clear picture of the direct effectsof GH on hepatic lipid processing is clouded by the fact that GH also alters whole body insulin sensitivity, insulin production and substrate availability (glucose and free fatty acids), all of wich are confirmed modulators of hepatic lipid metabolism. Separating out the relative roles of GH and insulin is further complicated by the fact that insulin, as well as GH, supports hepatic GH signaling and insulin-like growth factor I (IGF-I) production, and IGF-I and insulin serve as negative feedback regulators of GH secretion. Given the complex interrelationship between GH and insulin, experimental alteration in the output or signaling of one will inevitably lead to changes in the other. In order to circumvent these problems, the proposed series of experiments will take advantage of unique genetically engineered mouse models, developed by our laboratory, that clamp GH and insulin input to the liver. In this proposal, we will use genetically engineered animal models to achieve 1) controlled elevation of both GH and insulin, 2) high/normal GH in the absence of hepatic insulin signaling and 3) high/normal insulin in the absence of hepatic GH signaling. These in vivo models will be used in conjunction with primary hepatocyte cultures to address the following SPECIFIC AIMS: A) Determine if GH modifies insulin-mediated changes in hepatic lipid metabolism, B) Test if insulin is essential for GH-mediated regulation of hepatic lipid metabolism, and C) Examine the impact of adult-onset hepatic GH resistance on lipid metabolism. The knowledge gained will aid in the better understanding of the development, progression, diagnosis and treatment of metabolic diseases.